Polymorphic forms of tegaserod maleate

Abstract

Provided are crystalline forms of tegaserod maleate and processes for the preparation thereof.

1 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 15.7, 16.9, 17.2, 24.1, 24.6 and 25.2±0.2 degrees two theta comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in n-propanol, with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the crystal form.    
   
   
       2 . The process of  claim 1 , wherein before combining the slurry with maleic acid, the slurry is heated to a temperature of from about room temperature to about 70° C.  
   
   
       3 . The process of  claim 2 , wherein the temperature is from about 60° C. to about 65° C.  
   
   
       4 . The process of  claim 19 , wherein the mixture is cooled to room temperature.  
   
   
       5 . The process of  claim 1 , wherein the maleic acid is added as a solution with the same solvent used to form the slurry.  
   
   
       6 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 15.7, 16.9, 17.2, 24.1, 24.6 and 25.2±0.2 degrees two theta comprising: 
 a. combining tegaserod maleate crystalline form characterized by an X-ray diffraction pattern with peaks at about 8.7, 15.6, 16.0, 22.2 and 25.3±0.2 degrees two theta with ethyl acetate and n-propanol to obtain a mixture;    b. heating the mixture to a temperature of about 100° C. to reflux;    c. cooling the mixture to about room temperature or less; and    d. recovering the crystal form.    
   
   
       7 . The process of  claim 6 , wherein the mixture is heated to a temperature of about 100° C.  
   
   
       8 . The process of  claim 6 , wherein the mixture is cooled to a temperature of about 10° C.  
   
   
       9 . A process for crystallizing tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 15.7, 16.9, 17.2, 24.1, 24.6 and 25.2±0.2 degrees two theta from a solution of tegaserod maleate, ethyl acetate and n-propanol.  
   
   
       10 . The process of  claim 9 , wherein the ethyl acetate used is in a ratio of about 1:1 to about 1:3 by volume to n-propanol used.  
   
   
       11 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 5.4, 6.0, 6.6 and 10.8±0.2 degrees two theta, comprising spray drying a solution of tegaserod maleate in a solvent selected from the group consisting of: amines, amides, ketones and mixtures thereof with C 1 -C 8  alcohols or water.  
   
   
       12 . The process of  claim 11 , wherein the solvent is selected from the group consisting of: N-methyl-2-pyrrolidine or mixture thereof with methanol, N,N-dimethylformamide, and a mixture of acetone and water.  
   
   
       13 . The process of  claim 11 , wherein the solution is spray-dried at an inlet temperature of from about 30° C. to about 200° C.  
   
   
       14 . The process of  claim 13 , wherein the solution is spray-dried at an inlet temperature of from about 50° C. to about 200° C.  
   
   
       15 . The process of  claim 14 , wherein the solution is spray-dried at an inlet temperature of from about 50° C. to about 150° C.  
   
   
       16 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 5.4, 6.0, 6.6 and 10.8±0.2 degrees two theta, comprising grinding a mixture of tegaserod hemi-maleate hemihydrate with maleic acid.  
   
   
       17 . The process of  claim 16 , wherein, the tegaserod hemi-maleate hemihydrate is present in a ratio of about 1:1 weight /volume of maleic acid.  
   
   
       18 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 5.4, 6.0, 6.6 and 10.8±0.2 degrees two theta, comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in a solvent selected from the group consisting of: ethyl acetate, diisopropyl ether [DIPE], 2-methyl-THF, water, acetonitrile, n-butanol, sec-butanol, methyl isobutyl ketone, toluene, heptane, MEK or a mixture thereof, with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the crystal form.    
   
   
       19 . The process of  claim 18 , wherein before combining the slurry with maleic acid, the slurry is heated to a temperature of from about room temperature to about 70° C.  
   
   
       20 . The process of  claim 19 , wherein the temperature is from about 60° C. to about 65° C.  
   
   
       21 . The process of  claim 19 , wherein the mixture is cooled to room temperature.  
   
   
       22 . The process of  claim 18 , wherein the maleic acid is added as a solution with the same solvent used to form the slurry.  
   
   
       23 . The process of  claim 18 , wherein the mixture is treated with an ultrasound probe (sonicator).  
   
   
       24 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 6.6, 7.9, 8.9, 19.7, 21.8, 23.0, 23.9, 25.3 and 27.2 degrees two-theta, ±0.2 degrees two-theta comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in methanol, with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the obtained crystal form.    
   
   
       25 . The process of  claim 24 , wherein before combining the slurry with maleic acid, the slurry is heated to a temperature of from about room temperature to about 70° C.  
   
   
       26 . The process of  claim 25 , wherein the temperature is from about 60° C. to about 65° C.  
   
   
       27 . The process of  claim 25 , wherein the mixture is cooled to room temperature.  
   
   
       28 . The process of  claim 24 , wherein the maleic acid is added as a solution with acetone.  
   
   
       29 . A process for crystallizing tegaserod maleate characterized by an X-ray diffraction pattern with peaks at about 6.6, 7.9, 8.9, 19.7, 21.8, 23.0, 23.9, 25.3 and 27.2±0.2 degrees two-theta from a solution of tegaserod hemi-maleate hemihydrate, maleic acid and methanol.  
   
   
       30 . The process of  claim 29 , wherein maleic acid used is in a ratio of about 1:10 to about 1:13 weight/volume to methanol used.  
   
   
       31 . A crystalline form of tegaserod maleate characterized by X-ray powder diffraction peaks at about 6.6, 7.9, 8.9, 19.7 and 27.2±0.2 degrees two-theta, wherein the crystalline form is substantially free of a peak at about 10.3±0.2 degrees two theta.  
   
   
       32 . The crystalline form of  claim 31 , further characterized by X-ray powder diffraction peaks at about 21.8, 23.0, 23.9 and 25.3±0.2 degrees two-theta.  
   
   
       33 . The crystalline form of  claim 31 , wherein the crystalline form has an X ray diffraction pattern as substantially depicted in  FIG. 8 .  
   
   
       34 . The crystalline form of  claim 31 , wherein the peak at about 10.3±0.2 degrees two theta is absent.  
   
   
       35 . The crystalline form of  claim 31 , containing less than about 5% of any other crystalline form of tegaserod maleate by weight.  
   
   
       36 . The crystalline form of  claim 35 , containing less than about 1% of any other crystalline form of tegaserod maleate by weight.  
   
   
       37 . The crystalline form of  claim 36 , free of detectable peaks at about 7.0, 10.3, 13.7, 20.7 and 23.2±0.2 degrees two theta.  
   
   
       38 . The crystalline form of  claim 31 , which is anhydrous.  
   
   
       39 . The crystalline form of  claim 31 , which has a weight loss of about 0.1% by weight at the range of about 25° C. to about 200° C., as measured by TGA.  
   
   
       40 . A pharmaceutical composition comprising the crystalline form of  claim 31 , and a pharmaceutically acceptable excipient  
   
   
       41 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern having peaks at about 10.3, 16.1, 16.5, 17.1, 20.3, 22.0 and 25.3±0.2 degrees two theta comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in iso-propyl alcohol (IPA), with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the crystal form.    
   
   
       42 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern having peaks at about 8.7, 15.6, 16.0, 22.2 and 25.3±0.2 degrees two theta comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in ethanol/water, with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the crystal form.    
   
   
       43 . A process for preparing crystalline tegaserod maleate characterized by an X-ray diffraction pattern having peaks at about 15.6, 16.0, 22.5, 25.5 and 29.3±0.2 degrees two theta comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in ethanol, with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the crystal form.    
   
   
       44 . A process for preparing tegaserod maleate Form M comprising: 
 a. combining a slurry of tegaserod hemi-maleate hemihydrate in acetone, with maleic acid to obtain a mixture;    b. maintaining the mixture; and    c. recovering the crystal form.    
   
   
       45 . A process for crystallizing Form M from a solution of tegaserod maleate and a mixture of ethyl acetate and acetonitrile.